Prognostic Value of FST and Relevance to Immune Infiltration in Head and Neck Squamous Cell Carcinoma

ABSTRACT Background Immunotherapy response rates in head and neck squamous cell carcinoma (HNSCC) are limited by multiple factors. Tumor cell‐derived follistatin (FST) has been linked to immunotherapy resistance, but the underlying mechanisms remain poorly understood. This study aimed to investigate the prognostic value of FST and its associations with tumor‐infiltrating immune cells in HNSCC. Methods Bioinformatic analyses were performed using TCGA, GEO, TIMER 2.0, and CIBERSORT to explore correlations between FST expression and immune cell infiltration. Serum FST levels in HNSCC patients were measured by ELISA in 44 patients. Multiplex immunofluorescence (MIF) was used to detect FST, activin A (Act‑A), and immune cell markers in 110 HNSCC tissues. MIF images were analyzed using the Akoya Vectra Polaris system and Inform software. Survival analysis was conducted using the Kaplan–Meier method. Results High FST expression (FST high ) was significantly associated with poor progression‐free survival (PFS) and overall survival (OS). The percentage of FST + tumor cells was negatively correlated with the densities of CD8 + T cells, Tfh cells, and tertiary lymphoid structures (TLSs). The distance between CD8 + T cells and tumor cells was positively associated with FST expression. Act‐A, the primary binding protein of FST, is co‐expressed with FST and exhibits similar prognostic and immune‑infiltration patterns. Conclusion FST may serve as a novel prognostic biomarker and a predictor of immunotherapy responsiveness in HNSCC.